Targeted radiotherapy extends survival in metastatic castration-resistant prostate cancer
An investigational targeted radioligand therapy improved outcomes for certain men with advanced prostate cancer, according to randomized phase 3 study results to be presented during the plenary session of the virtual ASCO Annual Meeting.
The addition of lutetium-labeled PSMA-617 (Novartis) to best standard care significantly prolonged OS and PFS for men with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant disease.
The agent — commonly called 177Lu-PSMA-617 — also appeared well-tolerated.
The findings support adoption of 177Lu-PSMA-617 as a new treatment option for this patient population pending FDA review, according to Michael J. Morris, MD, clinical director of the genitourinary medical oncology service and prostate cancer section head in the division of solid tumor oncology at Memorial Sloan Kettering Cancer Center.
“A sizable number of men face the dilemma of what to do when they have completed androgen receptor-directed therapies and chemotherapy and their disease is still growing,” Morris told Healio. “There is no group of men with prostate cancer in higher need, and this introduces a life-prolonging therapy for them.”
Therapeutic options for metastatic castration-resistant prostate cancer include targeted therapies, chemotherapy and androgen receptor blockers. However, few effective and durable treatments exist, and approximately 85% of men die within 5 years of diagnosis.
PSMA — a transmembrane protein — is highly expressed by approximately 80% of men with prostate cancer, including those with metastatic disease.
However, expression on normal cells is limited. Consequently, Morris said, this phenotypic biomarker is “an excellent target” for both PET imaging and targeted systemic radiation treatment, known as radioligand therapy.
During radioligand therapy, a targeting compound that binds to markers expressed by tumors is combined with a radioactive isotope. This approach allows for targeted delivery of radiation to the tumor and surrounding microenvironment while limiting damage to nearby healthy tissue.
PSMA-617 targets PSMA with high affinity and delivers a payload of lutetium-177, a beta particle-emitting radioactive metal. When the drug carrying the lutetium-177 payload binds to PSMA, the whole molecule is internalized by the cell, where the cell is exposed to a lethal dose of radiation.
Morris and colleagues conducted the international, open-label VISION trial to assess the efficacy and safety of 177Lu-PSMA-617 for men with PSMA-positive, metastatic castration-resistant prostate cancer whose disease progressed after treatment with at least one androgen receptor pathway inhibitor and one or two taxane regimens.
Central review of 68 Ga-PSMA-11 scans determined PSMA positivity.
“This is the first time we have a personalized approach in prostate cancer using a scan rather than, let’s say, a genetic test for olaparib [Lynparza; AstraZeneca, Merck],” Morris said. “We used the scans to make sure patients’ cancer actually had the target so they are optimized to benefit from treatment, and that is a great move for the field.”
The trial included 831 men deemed inappropriate for additional chemotherapy. Enrollment occurred between June 4, 2018, and Oct. 23, 2019.
Morris and colleagues assigned 551 men to investigator-chosen best standard care plus 177Lu-PSMA-617, administered at a dose of 7.4 GBq via IV infusion every 6 weeks for four cycles. Responders with residual disease could receive an additional two cycles. The other 280 men received investigator-determined best standard care alone, excluding cytotoxic chemotherapy and radium Ra 223 dichloride (Xofigo, Bayer).
Treatment groups were balanced with regard to baseline characteristics and demographics.
Radiographic PFS — assessed by independent central review per Prostate Cancer Clinical Trials Working Group 3 criteria — and OS served as alternate primary endpoints. Key secondary endpoints included objective response rate, disease control rate and time to first symptomatic skeletal event.
Median follow-up was 20.9 months.
Men assigned 177Lu-PSMA-617 achieved significantly longer median radiographic PFS (8.7 months vs. 3.4 months; HR = 0.4; 99.2% CI, 0.29-0.57) and OS (15.3 months vs. 11.3 months; HR = 0.62; 95% CI, 0.52-0.74).
Morris described the relative improvement as more favorable than he anticipated, considering the original approvals for chemotherapy for castration-resistant prostate cancer were based on a 20% improvement in OS.
“This is a very good result,” Morris said. “Even though the difference in median survival was 4 months, I have patients who have had very durable responses with good quality of life, and they are not on any treatment right now. This is truly a life-saving therapy for those folks. They otherwise would have died or gone on to palliative care, but now they have a viable treatment option.”
Analysis of all key secondary endpoints revealed significant benefit with the 177Lu-PSMA-617 regimen, including ORR (29.8% vs. 1.7%), disease control rate (89% vs. 66.7%) and median time to first symptomatic skeletal event (11.5 months vs. 6.8 months; HR = 0.5).
The most common adverse events observed during the trial included fatigue (49.1% for experimental regimen vs. 29.3% for control), bone marrow suppression (47.4% vs. 17.6%), dry mouth (39.3% vs. 1%) and nausea/vomiting (39.3% vs. 17.1%).
Researchers reported a higher rate of grade 3 to grade 5 treatment emergent adverse events in the experimental group (52.7% vs. 38%). These events included bone marrow suppression (23.4% vs. 6.8%) — the most clinically relevant being anemia (13%) and platelet count decline (8%) — fatigue (7% vs. 2.4%) and kidney effects (3.4% vs. 2.9%). No cases of dry mouth were high grade and only 1.5% of nausea/vomiting cases were high grade, Morris said.
“We observed no new signals for this drug or radioligand therapy in general,” Morris said. “We would consider these events to be pretty much as expected for this type of therapy and, considering it makes men live longer, it’s a pretty good balance.”
Novartis officials intend to submit these data to regulatory authorities.
Two large phase 3 studies are getting underway to evaluate 177Lu-PSMA-617 as treatment for men with earlier-stage prostate cancer.
One will assess the therapy for men with metastatic castration-resistant prostate cancer who have not had chemotherapy. Another will evaluate the addition of 177Lu-PSMA to androgen deprivation therapy and androgen receptor-directed therapy of physician’s choice for men with newly diagnosed metastatic castration-sensitive disease.
“There is good reason to be optimistic, because most therapies that start out in late populations end up being positive in earlier populations,” Morris told Healio. “However, we have to remain balanced and have the equipoise to say it’s a question that needs to be asked.”
This trial is clearly important. Men in this trial had castration-resistant metastatic prostate cancer, so they had disease that grew even when testosterone in the body already had been reduced to very low levels, and despite receiving one to two prior taxane regimens. This trial shows an alternative to traditional therapies by using radiation targeted to PSMA, so it can be delivered directly to the prostate cancer cells. By doing that, survival was significantly improved. Use of this PSMA radioligand therapy — if it obtains regulatory approval — could indeed become an important treatment option for these men with refractory disease.
Perspective
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Perspective
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The results of the VISION trial represent a paradigm shift in the precision treatment of advanced prostate cancer. 177Lu-PSMA-617 is a completely new class of therapy, and the trial shows it improves patient outcomes compared with best standard of care. This is a hugely important moment for men with prostate cancer and their families.
Although the science behind this is highly complex — requiring decades of study by hundreds of researchers — the concept is fairly simple. The trial shows we can use PSMA — a protein that is specifically on the surface of prostate cancer cells — as a target. We can find them wherever they are in the body and send a targeted “radionuclide” right to those cells to destroy them.
Although the method that molecule uses to target the cancer is similar to a heat-seeking missile, that analogy really doesn’t do justice to the breakthrough we have here: This is the equivalent of killing cancer with a sniper rifle instead of a bomb. The radiation does not extend far beyond the cancer cell itself, so damage to surrounding tissue is minimal. In the trial, men who received precision therapy with 177Lu-PSMA-617 lived longer — and had less disease progression — than men treated with best standard of care.
The research community at Prostate Cancer Foundation (PCF) is bubbling with excitement. This incredibly meaningful breakthrough result is the culmination of 25 years of investment and 80 investigations funded by PCF in PSMA-targeted diagnostics and therapeutics. This is the kind of scientific rigor it takes to build the foundational science that allows something completely revolutionary, like PSMA-targeted radiopharmaceuticals, to be in contention to overtake the standard of care.
PCF first identified this as a promising treatment in 1994, the year after we opened our doors. The implications for men with advanced prostate cancer and their families, and for the field of prostate cancer at large, are profound.
Six months ago, the FDA approved PSMA imaging. Now we have these very promising results of PSMA-targeted therapy. The decades can feel long — to move from early laboratory studies to large, international clinical trials like VISION — but the science ultimately comes through, and ultimately will mean more birthdays and time with loved ones for men with prostate cancer. The VISION trial is the beginning of a journey to optimize delivery of this treatment. PCF is continuing to fund research into how to predict patient responses to 177Lu-PSMA-617 and to combine it with other treatments to further improve outcomes.
Prostate Cancer Foundation
Perspective
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This trial is clearly important. Men in this trial had castration-resistant metastatic prostate cancer, so they had disease that grew even when testosterone in the body already had been reduced to very low levels, and despite receiving one to two prior taxane regimens. This trial shows an alternative to traditional therapies by using radiation targeted to PSMA, so it can be delivered directly to the prostate cancer cells. By doing that, survival was significantly improved. Use of this PSMA radioligand therapy — if it obtains regulatory approval — could indeed become an important treatment option for these men with refractory disease.
Michigan Medicine
Perspective
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This in an important study looking at a molecular target, PSMA, against which specific radiation can be delivered, and it gives new hope to men with advanced prostate cancer. Androgen deprivation is the mainstay of therapy for advanced prostate cancer, but the cure rate is low and patients eventually become castrate resistant. Despite the numerous treatment options for metastatic castration-resistant prostate cancer, the impact on survival is less than optimal. There is a need to more closely tailor therapies to individual patient profiles. The identification of a new molecular target may improve tailored treatment.
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Morris MJ, et al. Abstract LBA4. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.